Beyond the Identification of Transcribed Sequences: Functional and Expression
Analysis

9th Annual Workshop, October 28-31, 1999

Co-sponsored by the U.S. Department of Energy

BORSANI

A tale of two diseases

Giuseppe Borsani

Tigem - Telethon Institute of Genetics and Medicine, Milano - Italy

EST database mining led to the identification of four novel members of a novel
amino acid transporter family (Solute Carrier Family 7, SLC7). The chromosomal
assignment of the genes revealed that they represent positional candidates for
lysinuric protein intolerance (LPI) and cystinuria type III (CSNU3) two human
inherited disorders due to impaired amino acid transport.

LPI is an autosomal recessive multisystem disorder, caused by a defective
cationic amino acid (CAA) transport at the basolateral membrane of epithelial
cells in kidney and intestine. After weaning, LPI patients present poor feeding,
vomiting and failure to thrive. A severe pulmonary complication and episodes
of metabolic imbalance may lead to death. Two of the new transcripts we have
identified, SLC7A7 and SLC7A8 map within the LPI critical region on chromosome
14q11.2, and are located on the same YAC. Analysis of both transcripts identified
mutations in the SLC7A7 gene only.

CSNU3 is a heritable disorder of amino acid transport, transmitted as an autosomal
recessive trait, with an overall prevalence of approximately 1 in 7,000. It
is due to the defective transport of cystine and dibasic amino acids through
the epithelial cells of the renal tubule and intestinal tract. Cystine has a
low solubility, and its precipitation results in the formation of calculi in
the urinary tract, which leads to obstruction, infections, and ultimately renal
insufficiency. Again, two transcripts belonging to the SLC7 gene family
were found to map within a small critical region on chromosome 19q13.1. Sequence
analysis in CSNU3 revealed that the disease is due to mutations in the SLC7A9
gene only.

Preliminary data provide evidences of additional members of this gene family
and suggest the existence of two homologous genes clusters on chromosome 14
and 19.